PROJECT SUMMARY/ABSTRACT In the U.S., about 12% of women have impaired fecundity and 7% of couples have infertility. In women, the leading causes are increasing age, ovulatory disorders, endometriosis, and tubal factor, and in couples, about 1/3 of infertility is due to female factors, 1/3 to male factors, and 1/3 to both. As mechanisms underlying the causes of infertility are largely wanting, treatments are mostly empiric. Infertile women who conceive spontaneously or with fertility therapies are at increased risk of adverse pregnancy outcomes due mainly to implantation and placenta disorders, with life-long effects on the health of children and adults born from these pregnancies. Thus, understanding mechanisms underlying reproductive success and compromise at the genomic, molecular, and cellular levels is critical to fertility and the health and well-being of this and future generations. Moreover, building a sustainable pipeline of junior investigators in this field and engaging investigators from multiple disciplines with diverse expertise are essential components to unravel the complexities of successful reproduction with translation to improving reproductive health more broadly. These are core principles of our NIH National Center for Translational Research in Reproduction and Infertility (NCTRI) at the University of California San Francisco (UCSF), funded since 2007 and for which this renewal proposal is submitted. The Specific Aims of our renewal application (overall) are: 1. to advance research in reproductive science and medicine through transdisciplinary collaboration and scientific and technologic innovation with the goal of improving human reproductive health and fertility 2. to serve as a national resource to inspire, mentor and train students, fellows, and junior scientists in reproduction and infertility research and to nurture their career development long-term 3. to communicate and be a national resource regarding the importance of reproductive research and its relevance to reproductive health and fertility for the public, health care professionals, and patients Our NCTRI Center for Research, Innovation and Training in Reproduction and Infertility at UCSF has 4 projects led by an experienced team of investigators/mentors and brings together expertise in clinical medicine, basic and translational science, precision medicine, genomics/eipgenomics, and advanced technologies focused on reproductive biology, oocyte aging, implantation, and placental development. Moreover, it provides a rich environment for trainees and outreach to the community about innovations in reproductive science and medicine. Our projects use advanced technologies and ?omics? approaches, animal models and human tissues and cells, and integrate well-annotated, relevant human phenotypic and clinical data to inform our studies. Our immediate goals are to determine epigenetic regulation of processes resulting in successful reproduction or infertility. Our long-term goals are to develop diagnostics and targeted therapies to alleviate infertility and poor reproductive outcomes and enhance the well-being of those with infertility and reproductive compromise.